F. G. West

New efficient iterative approaches to polycyclic ethers

The imposing structures of the marine polyether ladder toxins have inspired synthetic chemists to develop many clever methods for assembling these complex skeletons. One intriguing strategy is to use a short and reliable sequence of reactions to build successive rings in an iterative fashion. The ideal approach should tolerate variation in ring size and substitution at the bridgehead positions. This paper offers an overview of recent progress in this field.

Cyclization of Cross-Conjugated Trienes: The Vinylogous Nazarov Reaction

Cross-conjugated trienoates can be readily prepared from 1,4-pentadien-3-one precursors via a 2-step process: 1,2-addition of lithiated ethynyl ethyl ether followed by rearrangement of the resulting propargylic alcohol with catalytic VO(acac)(2). Treatment of the trienoates with stoichometric (TiCl(4)) or catalytic (Sc(OTf)(3)) Lewis acid provided conjugated alkylidenecyclopentenes via an apparent vinylogous Nazarov cyclization.

Olefination of α,α'-divinyl ketones through catalytic Meyer-Schuster rearrangement.

The direct olefination of 1,4-dien-3-ones remains a synthetic challenge. A two-step protocol, employing acetylide addition followed by catalytic Meyer-Schuster rearrangement has been developed for the olefination of 1,4-pentadien-3-ones to afford [3]dendralenes. Many of the traditional methods for the Meyer-Schuster rearrangement of alkynyl carbinols are not suitable with these highly unsaturated substrates because of their acid sensitivity. Unexpected reactivity during attempted rearrangement, including Nazarov-type electrocyclizations, is presented, along with conditions to promote the Meyer-Schuster rearrangement of ethoxyacetylene adducts using catalytic VO(acac)(2).

Coumarin derivatives and breast-feeding

Coumarin derivatives are the anticoagulants most widely used in the United States. These agents are relatively contraindicated during pregnancy, and the use of these drugs in breast-feeding women remains controversial. Much of the confusion regarding the passage of these agents into breast milk might stem from the fact that different agents possess significantly different chemical properties. A review of the chemical structure of different coumarin derivatives, as well as available clinical evidence, suggests that warfarin sodium is not excreted into breast milk, and can be safely given to women requiring therapeutic anticoagulation postpartum. For the rare patient who cannot tolerate warfarin sodium, the use of dicumarol, rather than anisindione, is preferred.

A short, enantioselective synthesis of (−)-epilupinine from proline via a spirocyclic ammonium ylide

Abstract Diazoketone 5b, available in one step from proline benzyl ester, underwent conversion to quinolizidine 8b with high diastereoselectivity (19:1 8b/7b) and in surprisingly high enantiomeric excess (75%). The key step presumably occurs via spirocyclic ylide 6b, which undergoes [1,2]-shift with retention. Rearrangement product 8b was converted to (−)-epilupinine 2 via an efficient, 3-step sequence.

Intermolecular [3 + 3]-cycloadditions of azides with the Nazarov intermediate.

Tetrasubstituted 1,4-dien-3-ones undergo Nazarov cyclization at low temperature, followed by reaction with organic azides via an apparent [3 + 3]-cycloaddition to give bridged bicyclic triazenes. These products do not appear to be intermediates in the previously described Schmidt-type process to furnish dihydropyridones. The reaction typically occurs with high diastereoselectivity.

Expedient route to the tigliane-daphnane skeleton via oxonium ylide [1,2]-shift.

A short, stereoselective approach to the fused tricyclic carbon skeleton found in the tigliane and daphnane classes of diterpene natural products is described. Convergent coupling of the A- and C-rings, followed by diastereoselective cerium enolate addition and formation of a double acetal set the stage for generation of an oxonium ylide via a transient metallocarbene. An efficient Stevens [1,2]-shift furnished the 7-membered B-ring, possessing the bridgehead oxygenation pattern found in the natural systems.

Homologous Mukaiyama Reactions via Trapping of the Nazarov Intermediate with Silyloxyalkenes

Treatment of 1,4-pentadien-3-ones and silyloxyalkenes with BF(3)·OEt(2) at room temperature or lower initiates a domino process consisting of sequential 4π electrocyclization and capture of the resulting cyclopentenyl cation by the electron-rich trap. The overall process furnishes 1,4-dicarbonyl products containing highly substituted cyclopentanones in good yields and with the establishment of up to five new stereocenters.

Nazarov reactions of vinyl cyclopropylamines: an approach to the imino-Nazarov problem.

Dichlorocyclopropanation of 2-amino-1,3-dienes affords 1-alkenyl-1-amino-2,2-dichlorocyclopropanes which undergo silver-assisted 2-π electrocyclic opening to furnish 3-aminopentadienyl cations. Nazarov-type cyclization of these intermediates leads to cyclopentenone iminium salts, which provide allylic amines upon reduction. This process, the imino version of the traditional Nazarov reaction, can also be combined with an interrupted Nazarov domino process to give polycyclic amines.

Radiopharmacological evaluation of 6-deoxy-6-[18F]fluoro-D-fructose as a radiotracer for PET imaging of GLUT5 in breast cancer.

INTRODUCTION Several clinical studies have shown low or no expression of GLUT1 in breast cancer patients, which may account for the low clinical specificity and sensitivity of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) used in positron emission tomography (PET). Therefore, it has been proposed that other tumor characteristics such as the high expression of GLUT2 and GLUT5 in many breast tumors could be used to develop alternative strategies to detect breast cancer. Here we have studied the in vitro and in vivo radiopharmacological profile of 6-deoxy-6-[(18)F]fluoro-D-fructose (6-[(18)F]FDF) as a potential PET radiotracer to image GLUT5 expression in breast cancers. METHODS Uptake of 6-[(18)F]FDF was studied in murine EMT-6 and human MCF-7 breast cancer cells over 60 min and compared to [(18)F]FDG. Biodistribution of 6-[(18)F]FDF was determined in BALB/c mice. Tumor uptake was studied with dynamic small animal PET in EMT-6 tumor-bearing BALB/c mice and human xenograft MCF-7 tumor-bearing NIH-III mice in comparison to [(18)F]FDG. 6-[(18)F]FDF metabolism was investigated in mouse blood and urine. RESULTS 6-[(18)F]FDF is taken up by EMT-6 and MCF-7 breast tumor cells independent of extracellular glucose levels but dependent on the extracellular concentration of fructose. After 60 min, 30±4% (n=9) and 12±1% (n=7) ID/mg protein 6-[(18)F]FDF was found in EMT-6 and MCF-7 cells, respectively. 6-deoxy-6-fluoro-d-fructose had a 10-fold higher potency than fructose to inhibit 6-[(18)F]FDF uptake into EMT-6 cells. Biodistribution in normal mice revealed radioactivity uptake in bone and brain. Radioactivity was accumulated in EMT-6 tumors reaching 3.65±0.30% ID/g (n=3) at 5 min post injection and decreasing to 1.75±0.03% ID/g (n=3) at 120 min post injection. Dynamic small animal PET showed significantly lower radioactivity uptake after 15 min post injection in MCF-7 tumors [standard uptake value (SUV)=0.76±0.05; n=3] compared to EMT-6 tumors (SUV=1.23±0.09; n=3). Interestingly, [(18)F]FDG uptake was significantly different in MCF-7 tumors (SUV(15 min) 0.74±0.12 to SUV(120 min) 0.80±0.15; n=3) versus EMT-6 tumors (SUV(15 min) 1.01±0.33 to SUV(120 min) 1.80±0.25; n=3). 6-[(18)F]FDF was shown to be a substrate for recombinant human ketohexokinase, and it was metabolized rapidly in vivo. CONCLUSION Based on the GLUT5 specific transport and phosphorylation by ketohexokinase, 6-[(18)F]FDF may represent a novel radiotracer for PET imaging of GLUT5 and ketohexokinase-expressing tumors.